Clonal hematopoiesis is associated with a seven‐year delay in the onset of Alzheimer’s disease in <i>APOE</i> ε4/ε4 cases

Abstract Background Recently, clonal hematopoiesis of indeterminate potential (CHIP) was found to be associated with a reduced risk of Alzheimer’s disease (AD) and somatic mutations found in the blood of CHIP carriers were also in microglia‐enriched brain samples (Bouzid et al., 2023, Nature Medicine ). We aimed to validate this finding in a larger dataset, explore the effect across APOE genotypes, and examine the association of CHIP with age‐at‐onset. Method Bouzid et al. (2023) analyzed the Alzheimer’s Disease Sequencing Project (ADSP) whole‐exome sequencing (WES) 10k subjects release and limited their analysis of this cohort to ε3/ε3 individuals, while we analyzed the new ADSP WES 20k subjects release and considered all APOE genotypes. We identified CHIP variants from joint‐called vcf files focusing on genes and variants provided in the previous study appendix. We further filtered variants requiring a median read depth above 30 among carriers and variant allele fraction below 40%. As in Bouzid et al., we restricted our analysis to European ancestry participants whose DNA was extracted from blood ( Table 1 ). Using the generalized linear model implemented in the statsmodel Python package, we tested the association with diagnosis (Binomial family) and age‐at‐onset (Gaussian family) across and by APOE genotype. Analyses were adjusted for sex, and the first 3 principal components accounting for genetic ancestry. Additionally, the analyses considering all APOE genotypes were adjusted for ε2 and ε4 dosages. Result We confirmed CHIP association with reduced AD risk in ε3/ε3 individuals (OR = 0.68 [0.54; 0.86], p = 0.0016), and observed a similar direction of effect across APOE genotypes (OR = 0.77 [0.64; 0.93]; p = 0.0058), except in ε2/ε3 ( Table 2 ). In addition, we found that CHIP was associated with 2.5 years delayed age‐at‐onset across APOE genotypes (b = 2.53 [1.27; 3.79]; p = 0.0001, Table 3 ), with a marked 7.7 years delayed onset in ε4/ε4 cases (b = 7.71 [2.66; 12.77]; p = 0.0028). Conclusion Taken together, these results provide stronger human genetic evidence that CHIP is associated with reduced AD risk and delayed age‐at‐onset, particularly in APOE ‐ε4 carriers. These findings corroborate the notion that rescuing microglial phagocytic capacity during aging may be a therapeutic avenue for AD, most notably in APOE ‐ε4 carriers.